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    Chapter 1 The Genetic Revolution

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    The Genetics Revolution LEARNING OUTCOMES ‘Ater complting tis chapter, you wil be able to ‘Describe the way in whicn modern genet doveloped. ‘+ List the man calular constituants invaived in ‘gene expression and action. * Give some examples of how ganetics has influenced modem medicine, agriculture, and ‘evolution, DNA (deoxyribonuceic acd) fs te molecule that encodes gone information The stings of for diferent cherical bases n DNA store genetic information ‘much the same way that stings of Os and 1 store information in computer code. (Sergey Men/Shutrsto) OUTLINE 1.1 The birth of genetics 1.2 After cracking the code : 1.3 Genetics today CHAPTER 1 Like begets like The Genetics Revolution 3 is form of faformation ence. Genet sek to understand Cites ate niin st gettin cre stom pret loping wii onic fm DNA gene acon wins brea caln andor manyfeuaton inp conga ino. These coc of genet archnom weno eae oecla. tcreiopmentl gene a population gence There pao Sint emmins these ef of gnc The sence af gence vs bom ut oer 10 years ago Since that time, genes hs profualychanged ur understanding fom th evel of Ue svi elo thatofaupuaon of rains ctlving ove millon yas in D0, Willan asm prominent th leg wrote presen tan "Dat darminaton ote oe of heredity wl pot mk moe Ganga tan cn te wordand ins ove vet atr,han any ote ance in ntl nowdge acne rescen’ Throughout hte ou wl ee he tala of Bass poco, Genet es Given e ec i oth he Vila sens an sry in gece Unt itches ewes ri thes of gent ann dogs, el ere same ofthe bs concep of ents at wee do ered ver lst 10 Jeu Ales Ute illo a ew expe a w gene analy bela apped to cea protien in biog apts ond man bea toy. You wil ce how contemporary ere in ena inte trates concep dsoeed dead ago wih xen ehnola rnc Yu Sitse tar geet tony va djuane id of inven nwich ned Covet areconinualyadvecing cr undersanding of te el wold 1.1 The Birth of Genetics Throughout recorded history, people around the world have understood that “like begets like.” Children resemble their parents, the seed from @ tree bearing flavorful fruit will in turn grow into a tree laden with flavor ful fruit, and even members of wolf packs show familial resemblances (igure 1-1). Although people were confident in these observations, they ‘were left to wonder as to the underlying mechanism. The Native Ameri ‘can Hopi tribe of the Southwestern United States understood thatif they planted a red kernel of maize in their fields, it would grow into a plant that also gave red kernels, The same was true for blue, white, or yellow kernels. So they thought of the kernel as a message to the gods in the Earth about the type of maize the Hopi farmers hoped to harvest. Upon receiving this message, the gods would faithfully return them a plant that produced kernels ofthe desired color. In the 1800s in Europe, horticulcuralists, animal breeders, and biolo- sists also sought to explain the resemblance between parents and off- spring. A commonly held view at that time was the blending theory of imheritance, or the belie that inheritance worked like the mixing of flu ids such as paints, Red and white paints, when mixed, give pink; and soa child of one tall parent and one short parent could he expected to grow to a middling height. While blending theory seemed to work at times, it twas also clear that there were exceptions, such as tall children born to parents of average height. Blending theory also provided no mechanism by which the “heredity fluids” it imagined, once mixed, could be sepa- ratod—the red and white paints cannot be reconstituted from the pink, ‘Thus, the longterm expectation of blending theory over many genera- FIGURE 1-1 Family groups inthe gray wot chow fall esombanoes ronal colorscneipatermg, tions of intermating among individuals is that all members ofthe popu [fan alvendonatrerOatty mages; oon) Bev McConre ation will come to express the same average value of a trait. Cleary, (ety mages} isnot how nature works. Human populations have people with a range of hacights, from short to tall, and we have not all narrowed in on a single average height despite the many generations that human populations have dwelled on Earth Gregor Mendel—A monk in the garden While the merits and failings of blending theory were being debated, Gregor Mendel, an Austrian monk, was working to understand the rules that govern the transmission of traits from parent to offspring after hybridization among different varieties of pea plans (Figure 1-2). The setting for his work was the monastery garden inthe town of Brinn, Austria (Brno, Czech Republi, today). From 1856 to 1863, Mendel cross-pollinated oF intermated different varieties ofthe pea plant. One of his experiments involved crosing pea variety with purple flowers to one ‘ith white flowers (Figure 13). Mendel recorded that the ist hybrid generation (One of Mendet’s experiments two fow copies Selt-poination 8 purple: 1 white 1.1 The Bith of Genetics 3 Gregor Mende! FIGURE 1-2 Gregor Mendel vas an ‘Asian monk who discovered the ws of Inertanen. James King Hoimas/Sionco Soueel FIGURE 1-3 The rating scheme for Mendes ‘experiment invvng the crossing of purle- and \file-fovrered varieties of pea plants. The purpie and white cies signi the gene variants for puple ‘8, white flower coin. Gamotes carry one gone ‘copy; the pants each carry two gene copes. The ‘x sgniies a cross-polnation between the purple and whitelovered plats 4 CHAPTER 1 The Genetics Revolution of offepring from this cross all had purple flowers, just like Merriete 1PeGruitestion one ofthe parents. There was no bending, Then, Mendel self WLR RLS pullinatd the first generation hybrid plants and grew a sec- ond generation of offspring. Among the progeny, he saw Vorsuche tiber Pfanzen-Hybriden. planes with purple flowers as well as plants with white flow- crs. OF the 929 plants, he recorded 705 with purple flowers, and 224 with white flowers (Figure 1-4). He observed that there were roughly 3 purple-flowered plants for every 1 white- flowered plant. How did Mendel explain his results? Clearly, blending the- ‘ory would not work since that theory predicts a uniform group, of first-generation hybrid plants with light purple flowers. So ‘Mendel proposed that the factors that control traits act like ‘eet mo particles rather than fluids and that these particles do not om pan ees blend together but are passed intact from one generation to ‘the next, Today, Mendel’s particles arc known as genes. Gea Cae it re ree tata Mendel proposed that each individual pea plant has two SSS SAAS SASS SS copies of the gene controlling flower color in each of the cells of se the plant body (somatic cells), However, when the plant forms me sex cells, or gametes (eggs and sperm), only one copy of the FIGURE 1-4 Excerpts fom Mendis 1866 pubicaton, Vrsuche Ober Parzen _Hybriden (Experiments on plant hybrics). [gustan abbey in Ole, Courtesy of the Masaryk Unveray, Mende Musou) gene enters ino these reproductive cells (see Figure 1-3). Then, Sin ‘when egg and sperm unite to start anew individual, once again there will be vwo copes of the flower color gene in each cell of the plant bod. “Mendel had some further insights. He proposed that the gene for flower color comes in two gene variant, or alleles one that conditions purple flowers and one that conditions white flowers. He pro posed that the purple allele of the flower color gene is dominant to the white allele such chat a plant with one purple allele and one white allele would have purple flowers. Only plants with two white alleles would have white flowers (see Figure 1-3). Mendel two conclusions, (1) that genes behaved like particles that do not blend together and (2) that one allele is dominant tothe other, enabled him to explain the lack of blending in the first-generation hybrids and the re- appearance of white-flowered plants in the second-generation hybrids with a 31 ratio of purple: to white-lowered plans. This revolutionary advance in our ‘understanding of inheritance will be ally discussed in Chapter 2 “How did Mendel ge ie right when so many ater’ before him were wrong? Mendel chose a good organism and good traits to stidy. The traits he studied were all controlled by single genes. Traits that are controlled by several genes, as many traits are, would not have allowed him to discover the laws of inheritance so easly. Mendel was also a careful observer, and he kept detailed records of each of his experiments. Finally, Mendel was a creative thinker capable of reasoning well beyond the ideas of his times, Mendel’ particulate theory of inheritance was published in 1866 isthe Pro- ceedings of the Natural History Society of Brinn (see Figure 1-4). At that time, his work was noticed and read by some other biologists, but its implications and importance went unappreciated for aver 30 years. Unlike Charles Darwin, whose discovery of the theory of evolution by natural selection made him’ world- renowned virtually overnight, when Mendel died in 1884, he was more or less ‘unknown in the world of science. As biochemist Erwin Chargaf putt, “There are people who scem tobe born in vanishing cap. Mendel was one of them.” |) KEY CONCEPT Grog Mendel domonstaod tat gras behave he paras | ana not tic, Mendel rediscovered As the legend goes, when the British biologist William Bateson (Figure 1-5) boarded a train bound for a conference in London in 1900, he had no idea how profoundly his world would change during the brief journey. Bateson carried with him a copy of Mende!’s 1866 paper on the hybridization of plant varieties. Bateson hhad recently learned that biologists in Germany, the Netherlands, and Austria had each independently reproduced Mendel's 3:1 ratio, and they each cited Mendel's original work. This trio had rediscovered Mende!'s laws of inheritance. Bateson needed to read Mendel’s paper. By the time he stepped off the train, Bateson had anew mission in life. He understood that the mystery of inheritance had been solved. He soon became a relentless apostle of Mendel's laws of inheritance. A few years later in 1905, Bateson coined the verm geneties—the study of inheritance. ‘The genetics revolution had begun. When Mendel’s laws of inheritance were rediscovered in 1900, a flood of new thinking and ideas was unleashed. Mendelism became the organizing principle for much of biology. There were many new questions to be asked about inher: tance. Table 1-1 summarizes the chronology of seminal discoveries made over the ‘coming decades and the chapters ofthis text that cover each of these topics. Let's look briefly ata few of the questions and their answers that transformed the bio logical sciences. Wherein the cell are Mendets genes? The answer came in 1910, when Thomas H. ‘Morgan at Columbia University in New York demonstrated that Mendel's genes are located on chromosomes-he proved the chromosome theary of inheritance. The idea was not new. Walter Sutton, who was raised on a farm in Kansas and later served 2s a surgeon for the US. army during WWI had proposed the chromosome theory of inheritance in 1903. Theodor Boveri, a German biologist, independently proposed it at the same time. It was a compelling hypothesis, but there were no experimental data to support it. This changed in 1910, when Morgan proved the ‘chromosome theory of inheritance using Mendelian genetics and the fruit fly a his ‘experimental organism. In Chapter 4 you will retrace Morgan's experiments that proved genes are on chromosomes, Can Mendelian genes explain the inheritance of continuously variable traits lke ‘human height? While 3:1 segregation ratios could be directly observed for simple traits like flower color, many traits show a continuous range of values in second- generation hybrids without simple ratios like 3:1. In 1918, Ronald Fisher, the British statistician and geneticist, resolved how Mendelian genes explained the inheritance of continuously variable traits like height in people (Figure 1-6). Fisher's core idea Continuous variation for height 1.1 The Birth of Genetics 5 William Bateson ‘gave genetics its name FIGURE 1-5 Wilam Bateson, the Betish zoologist and evoitionist who eiteduced the tm genetics forthe study Cf inertznes an promoted Mendel’s work. [SAUScionce Source} FIGURE 1-6 Students at the Connecticut Agriculture Collage n 1944 show a range of heights. Ronald Fsher proposed int ‘continuously varable rats tke human height re contled by multiple Mendolan genes. 4. ‘Blake, “Com and Men” Joural of Heresy 5, 7, 1944, 61-518), 6 CHAPTER 1. The Genetics Revolution I TABLE 1-1 Key Events in the History of Genetics Year Event Chapters 1865 Gregor Mendel showed chat trait are controlled by disree factors now known a genes 23 1869 Friedrich Miescher slated IA from the nucle of white blod cells 7 1903 Walter Suton and Theodor Boveri hypothesized that chromosomes are the hereditary elements 4 1905 Wiliam Bateson intoduced the term "genetis* forthe sey of nheriance. 2 1908 GH nly and Win Weinberg pops he Hardy-Weinberg the ounaion fr ppuaon 8 1910 Thomas H. Morgan demonstrated chat gones are located on chromosomes. 4 1913 _Alfed Stareevant made a genetic Iinkage map of the Drosophila X chromosome, the Fs genetic map a ‘P18 Ronald Fisher proposed that maliple Mendelian factors can explain consinuows variation for wits founding 1) thefield of quandtatve genetics 1951 Harviet Creighton and Barbara McClintock showed that crossing over is the eause of recombination. ‘416 {DAL Edward asm and Geors Beale prope he ot gine one pelypeplde hyped é 1944 Oswald Avery, Colin MacLeod, and Maclyn McCarty provided compelling evidence that DNAs the genetic 7 material in bacterial cel 1946 _Joshua Lederberg and Eaward Tatum discovered bacterial conjugation. 5 1948 Barbara McClintock discovered mobile elements (ransposons) that move from one place toanother inthe 15 genome. 1950 Erwin Chargaff showed DNA composition follows some simple rales for the relative amounts of A,,G,and'T. 7 1952 _Alfred Hershey and Martha Chase proved that DNA is the molecule that encodes genetic information, 7 1953 James Watson and Prancis Crick determined that DNA forms a double helix 7 1958 _ Matthew Meselson and Franklin Stahl demonstrated the semionservative nature of DNA replication, 7 1958 Jérdme Lejeune discovered that Down syndrome resulted from an extra copy of the 2ist chromosome. w 1961 Frangois Jacob and Jacques Monod proposed that enzyme levels in cells ae controled by feedback 1 ‘mechanisms. 1961 Marshall Nirenberg, Har Gobind Khorana, Sydney Brenner, and Francis Crick “cracked” the genetic cade. 9 1967 1968 Motoo Kimura proposed the neutral theory of mlecular evolution 38,20 1977 _ Fred Sanger, Walter Gilbert, and Allan Maxam invented methods for decermining the nucleotide sequences of 10 DNA molecules. 1980 Christiane NassleinVolhard and Eric F Wieschaus defined the complex of genes that regulate body plan 13 development in Drosophila 1989 _ Francis Collins and Lap-Chee Tsui discovered the gone causing cystic fibrosis 410 1993 Victor Ambrose and colleagues described the first microRNA. B 1995 First genome sequence ofa lving organism (Haemophilus influenzae) published 4 1996 First genome sequence of a eukaryote Saccharomyces cerevisiae) published. « 1998 _ First genome soquence of an animal (Canorhabis elegons) published. « 2000 First genome sequence ofa plant (Arabidopsis thaliana) published, 4 2001 The sequence ofthe human genome first published. 4 2006 Andrew Fite and Craig Mello win the Nobel prize for their discovery of gene silencing by double-stranded RNA. & 2012 John Gurdon and Shinya Yamanaka win the Nobel prize for their discovery that just four regulatory genes can 8, 12 convert adule cells into stem cells ‘The one-gene-one-enzyme model T a 7 8 conec g A & 8 Enzyme ¢ Substrate —E22°4 5 Omihing EMME» crnsine ERIM > sesiine was that continuous traits are each controlled by multiple Mendelian genes. Fisher's Insight is known as the multifactorial hypothesis. n Chapter 19, we wil dissect the ‘mathematical model and experimental evidence for Fisher's hypothesis. ‘How do genes function inside cls in a way that enables them 1 control diferent states for arrait ike flower color? in 1941, Edward Tatum and George Beadle proposed that genes encode enzymes. Using bread mold (Newrospora crassa) as their experi- ‘mental organism, they demonstrated that genes encod the enzymes that perform ‘metabolic functions within cells Figure 1-7) Inthe case ofthe pea plant, there is @ ‘gene that encodes an enzyme required to make the purple pigment in the cells ofa Flower. Tatum and Beadle's breakthrough became known as the one-gene-one- ‘enzyme hypothesis. Youll see how they developed this hypothesis in Chapter 6, Whats the physial narure ofthe gene? Are genes composed of protein, nucleic acid, or some other substance? In 1944, Oswald Avery, Colin Macl.cod, and Mac- lyn McCarty offered the first compelling experimental evidence that genes are made of deoxyribonucleic acid (DNA). They showed that DNA extracted from a virulent strain of bacteria carried the necessary genetic information to transform a nonvirulent strain into a virulent one. Youll earn exactly how they demon- strated this in Chapter ‘How can DNA molecules store information? In the 1950s, there was something of a race among several groups of geneticists and chemists to answer this ques: ‘on, In 1953, ames Watson and Francis Crick working at Cambridge University in England won that race. They determined that the molecular structure of DNA ‘was in che form of a double helix-two strands of DNA wound side-by-side in a spiral. Their structure of the double heli slike « twisted ladder (Figure 18). The sides of the ladder are made of sugar and phosphate groups. The rungs of the lad- der are made of four bases: adenine (A), thymine (T), guanine (G), and eyto- sine (C). The bases face the center, and each base is hydrogen bonded to the base facing itn the opposite strand. Adenine in one strand is always paired with thy- rine in the other by a double hydrogen bond, whereas guanine is always paired with cytosine by a triple hydrogen bond. The bonding specificity is based on the complementary shapes and charges of the bases. The sequence of A, T,G, and C represents the coded information carried by the DNA molecule. You will learn in Chapter 7 how this was all worked out. ‘How are genes regulated? Cells need mechanisms to turn genes on or fF in spe- cificcell and tissue types and a specific times during development. In 1961, Prancois Jacob and Jacques Monel made a conceptual breakthrough on this question. Work- ing on the genes necessary to metabelize the sugar lactose in the bacterium Eche- richia col, they demonstrated that genes have regulatory elements that regulate gene expression—that is, whether a gene is turned on or off (Figure 1-9). The regu- Tatory elements are specific DNA sequences to which a regulatory protein binds and ‘acts as either an activator or repressor of the expression ofthe gene. In Chapter 1, you will explore the logic behind the experiments of Jacob and Monod with E.coli, and in Chapter 12, you wll explore the details of gene regulation in eukaryotes. 4.4 The Birth of Genetios FIGURE 1-7 The ore-gere-ore- ‘enzyme model proposed that genes encode enzynos tat cary out Dlocherical functions within cols. Tatum and Beadle proposed this model ‘based on the study ofthe syrhesis of _argine en arr ac in the beat ‘mod Neurospors crassa, 7 8 CHAPTER 1 ‘The Genetics Revolution ‘The structure of DNA 0, FIGURE 1-8 (a) The doubie-holcal structure of DNA, showing the sugar-phosphate backbone in blue and pared bases in conn. (A ttoned ropresertaton of DNA ‘Showing how A always cas wih T and G wih C. Each row of dats botweon the basos represents a hycrogen bond. How i the information stored in DNA decoded to synthesize proteins? While the discovery of the double-helical structure of DNA was a watershed for biology, ‘many details were still unknown. Precisely how information was encoded into DNA and how it was decoded to form the enzymes that Tatum and Beadle had shown to be the workhorses of gene action remained unknown. Over the years 1961 through 1967, eams of molecular geneticists and chemists working in several ‘countries answered these questions when they “cracked the genetic code.* What this means is that they deduced how a string of DNA nucleotides, each with one ‘of four different bases (A, C, or G), encodes the set of 20 different amino acids that are the building blocks of proteins. They also discovered that there is a mes- senger molecule made of ribonucleic acid (RNA) that carries information in the DNA in the nucleus to the eytoplasm where proteins are synthesized. By 1967, the ‘basic flowchart for information transmission in cells was known. This flowchart is called hg i KEY CONCEPT The rediscovery of Mendets laws launched a new era in which | ganetiss resabved many undarrental questions abou the nature of tho gene and I the flow of genetic information within cells. During this - Shaaitebac racine. Genes have regulatory and coding regions Fapirperte 1.1 The Birth of Genetios FIGURE 1-9 The sinctie ofa protein-coding gene showing a regatory BNA coment (@GGCCR) to whiena regulatory protein binds, the promoter Fegan region where the RNA polymerase Direction of complex binds to intate rarscration, and 2 rerscrpion 8 proter-coding region eee Regulaiory Ste where me Proton coding, ‘lement’ FINApolymerase sequence complex binds ‘The central dogma of molecular biology In 1958, Francis Crick introduced the phrase “central dogma” to represent the flow of genetic information within cells from DNA to RNA to protein, and he drew a simple diagram to summarize these relationships (Figure 1-10a). Curi- ‘ously, Crick chose the word dogma thinking that it meant “hypothesis,” which was ‘hs intention, unaware that its actual meaning is “a belief that is to be accepted without doubt." Despite this awkward beginning, the phrase had an undeniable power and it has survived, Figure 1-10b captures much of what was learned about the biochemistry of inheritance from 1905 until 1967 Let’ review the wealth of knowledge that this ures. At the left, you sce DNA and a circular arrow representing the process by which a copy of the DNA js produced. This pro- cess enables each of the two daughter cells that result from cell division to have a Information transfer among biological molecules em ae FIGURE 1-10 (4) Ono version of Francis Crick’ sketch ofthe central dogma, showing information fow between biological molecues. The ckeuar artow roprosonts DNA repletion, the coal tralgnt arrow represents the raeesoton of DNA into INA, and the right aro the ransatton of ANA into protein. (o) More detaled sketch showing how the ‘wo stands ofthe DNA double hel are ndopendersyrepicated, how the two eran are clsassocated for ranserplon, anc how tha massanger RNA (ENA) Is translated Ito ‘roten at tho bosome, 10 CHAPTER 1 The Genetics Revolution ‘complete copy of all the DNA in the parent cell. In Chapter 7, you will explore the details ofthe structure of DNA and its replication. ‘Another arrow connects DNA to RNA, symbolizing how the sequence of base pairs in a gene (DNA) is copied to ay le. The process | Rem RDNA mooi le me cas of RA ee es a = ‘In Chapter 8, you'll discover how transcription is ince Crick proposed the central dogma, additional pathways of genetic infor- ‘mation flow have been discovered. We now know that there are classes of RNA. that do not code for proteins, instances in which mRNA is edited after transcrip- tion, and cases in which the information in RNA is copied back to DNA (see Chap- ters 8, 9, and 15). 1.2_ After Cracking the Code ‘With the basic laws of inheritance largely worked out by the end of the 19608, a new era of applying genetic analysis to a broad spectrum of biological questions flourished. To this end, much effort has been and continues to be invested in veloping the resources and tools to address these questions. Geneticists focused ‘heir research on a small number of species known as “model organisms” that are well suited for genetic analysis. They also developed an impressive array of tools for manipulating and analyzing DNA. Model organisms Geneticists make special use of a small set of model organisms for genetic analy- ‘the use of model organisms in biology was wryly expressed by Jacques Monod: “Anything found to be true of E.coli must also be tue of elephants." ‘As genctcs matured and focused on model organisms, Mende!’ pea plants fell tothe wayside, but Morgan's fruit les rose to prominence to become one of the most important model organisms for genetic research. New species were added tothe list. An inconspicuous litle plant that grows asa weed called Arabi- dopsis thaliana became the model plant species and a minute roundworm called Caenorhabditis elegans tat lives in compost heaps became a star of genetic analy- sisin developmental biology (Figure 1-1). What. 5a model organism? (SH thatare easy ‘are very convenient for research, So fruit flies are good, blue whales not so good. 2) is imperative because geneticists, ike Mendel, need wo cross n study their "8 Jacob and} Monod Cl pring Harbor Quane Symp. Bal 26, 1963, 383 1.2 After Cracking the Code 11 Model organisms are dispersed across the tree of ite Yeast ———— “Arabidopsis ‘Mycoplasma ‘ereata Becius subi Heleobacter pilon FIGURE 1-11 The te shows evolstonary relationships among the major groups of ‘organs: Bacteria, Archasa and Eukaryota (las, ung, anc anima). [ockws, fom on, {opnote Assocates/Scerce Photo Libary, inagebrokecn/SupeStock; © BickaraoAy} first and second-generation hybrids. The shorter the generation time, che sooner the experiments can be completed. 3) soul gone = ‘sel. As yu will earn in Chapter 15, some species have large genomes and others small genomes in terms Of the total numberof DNA basepairs. Much ofthe extra size of large genome spe- Cies is composed of repetitive DNA element between the genes. If a genetic s looking or genes these canbe more easily found in organisms with smaller genomes and fewer repetitive elements. (4) Organnms that ae easy to cross or mate and that produce large numbers of offspring are best. ‘As you ead this textbook, you will encounter certain organisms over and over ‘Organisms such as Escherichia coli (a bacterium), Saccharomyces cerevisiae (baker's yeast), Caenorhabditis elegans (nematode of roundworm), Drosophila melanogus ter (fruit fly), and Mus musculus (mice) have been used repeatedly in experiments and revealed much of what we know about how inheritance works. Model organ jms can be found on diverse branches ofthe tee of life (Gee Figure 1-11), repre senting bacteria, fungi, algae, plans, and invertebrate and vertebrate animals. 12 CHAPTER 1 The Genetics Revolution ‘This diversity enables each geneticist to use @ model best suited toa particular question. Each model organism has a community of scientists working on it who share information and resources, thereby facilitating each other's research ‘Mendes experiments were possible because he had several different varieties ‘of pea plants, each of which carried a different genetic variant for traits such as purple versus white flowers, green versus yellow seeds, or al versus dwarf stems. For each of the model species, geneticists have assembled large mumbers of variet- ies (also called strain or stocks) with special genetic characters that make them ‘useful in research. There ae strains of fruit lies that have trait variants such as red versus white eves. There are strains of mice that are prone to develop specific forms of cancer or ther disease conditions such as diabetes. For baker's yeast, there isa collection of nearly 5000 deletion secs, each ofthese having jst one sgene deleted from the genome. These stocks enable geneticists to study the func- tion ofeach gene by examining how yeast i affected when the gene is removed. Since baker's yeast has about 6000 total genes, this collect of 8000 deletion stocks covers most ofthe genes inthe genome ‘The different strains of each model organism are available to researchers through stock centers that maintain and distribute the strains. Lists of available stocks ae onthe internet (see Appendix B).To view an example for mouse stocks, 0 to the link ttp//jamice jaxorg/. Them, click the “Find JAX mice” button at the top ofthe page. Next, enter the word "black” in the search field and click the Search button. Now, click the *C57BL/6]" ink. You wil see an image and informe- tion on a commonly used C37-Black mouse strain. Other search terms such a3 “albino o obese” wil link you with strains with other features. KEY CONCEPT Wstgerte tudes oe patna nom tants Moc acer avai a hae ones toe bun sane onad | soot ocen Tools for genetic analysis Geneticists and biochemists have also created an incredible array of tools for char- acterizing and manipulating DNA, RNA, and proteins. Many of these tools are described in Chapter 10 or in other chapters relevant toa specific tool. There are 1 few themes to mention here. First, geneticists have harnessed the cell's own machinery for copying, pasting, ‘cutting, and transcribing DNA, enabling researchers to perform these reactions inside test tubes. The enzymes that perform each: is hhave been purified and are available to researcher radioactive element so that the DNA can be detected using a fluorescence or radi- ation detector. Second, geneticists have developed methods id the genes it ‘encodes. Here, cloning refers to making many copies ‘a DNA molecule, ‘The common way of doing this involves isolating a relatively small DNA molecule (up to a few thousand base pairs in length) from an organism of interest. The DNA molecule might be an entire gene or a portion of a gene. The molecule is inserted into a host organism (often E. coli) where its replicated many times by the host's DNA polymerase. Having many copies ofa gene is important fora vast Sete ee dreete camp, ch asics a as ee DESI 1.2 Alter Cracking the Code 13 ‘This process is called and itis possible, for instance, to trans- form genes from one & snome of another. The recipient species then becomes al igure 1-12 shows a tobacco plant in which a gene from the firefly was inserted, enabling the tobacco plant to emit light or glow in the dark. Fourth, geneticists have developed a large set of methods based on S9BMGINED |i este wo RNA moeciles) The two complementary strands of DNA inthe double el are bound tether ay hydrogen bonds, ether Cord = T-Thesebondseanbebraten by heat GMBH nt coos tion to gve two single stranded DNA molecles (Figure 1-3) When te solution iscone under controlled conditions, DNA molecules with complementary strands wil preferentially hyde wth one another DNA hybridization methods have tnebled many dacoveres Tor example the doned DNA of «gee can be tagged wih fluorescent ye and hen hyde eo chromosomes fied on a ncroseope Sl, evealing the chromosome on which the genes located (igure 1-13). ith, geneticists and biochemiss have developed mullipe methods for deter rnining the exact sequence ofall the Ne, Cs and Tin the genomes, chrome- Somes, or genes of an organism. The process used i decipher the enact sequence or as Cs Gand Ts ina DNA molecule called DNA wee nd thos alowed generis to read te language oie nally oer tela 20 years researchershave rated molecular nd mathema ica ols for analyaing the entre ge s “1 intel gmoniartc ayes ad cceCaper) Cewmewoshmesublelnciate Genetically modified tobacco and Stabe Expression o 1 Gane in lar Cae and Pansganie to assemble mind-boggling amounts of information on model organisms, including Pans" Sconce 294, 4778, 1985 886-250) the complete DNA sequence oftheir genome, iss of all their genes, catalogs of varie ants in these genes, data on the cell and tissue types in which cach gene is expressed, ‘and much more. To get an idea of what is available, try browsing Fly Base (http:!/ flybase.org/), the genomic daca site for the fruit ly (Gee also Appendix B). 8 KEY CONCEPT Progress in gonatios has both produced and been catalyzed bythe develogment of melocula ad mathematica too for Ue analysis of single (genes and whe genomes ‘Strands of nucleic acids hybridize to complementary sequences ay 5 f ay Heat Coot Denatire panes > FIGURE 1-18 (a) Te wo strands of the DNA double hal can be cssoclated by heat in aqueous solutone. Upon caaling under oontrllad condtons, strands associate, o:fybricize, wlth thor ‘complemen, (2) cloned copy ofthe human BAPX' gona was tagged wih a green fuorescent ove. “The fucrescenttagged DNA was then denatured and alowed to hybridize othe chromosomes ina ingle oa. The RLoescert-taggod clone hybrcized to the locaton en chromosome 4 (rer ‘uoroscert regions) whore the gone is located. (©. Tied and. Luk, "Mobscut oig, civornesoma mapping and devslopmental excresscn of BAP, @neval human homeabor contaning gene homalogous to Dasophiabagoion” Gene 203 2, 1997 225-258 Fig 6. @ Bret), 14 CHAPTER 1. The Genetics Revolution 1.3 Genetics Today In an interview in 2008, Princeton University geneticist Leonid Kruglyak remarked, “You have this clear, tangible phenomenon in which children resemble their parents. Despite whar students get told in clementary-school science, we just don'tknow how that works.” Although Kruglyak’s remark might seem disparaging to the progress made in the understanding of mheritance over the last 100 yeats, this was certainly not his intention. Rather, his remark highlights that despite the paradigm-shifting discov cries ofthe nineteenth and twentieth centuries, enigmas abound in genetics and the need for new thinking and new technologies has never been greater. Mendel, Morgan, Fisher, Watson, Crick, and many other others (see Table 1-1) delimited the foundation of the laws of inheritance, but the details that rest atop that foun dation remain obscure in many ways. The six feet of DNA in the single cell of a ‘human zygote encodes the information needed to transform hat cell into an adult, but exactly how this works is understood only in the sparsest detail. In this section, we will eview four recent advances in geneties~discoveries of enough importance and general interest that they were featured in the popular press. Reading about these discoveries will both reveal the power of genetics to answer critical questions about life and highlight how this knowledge can be applied to addressing problems in society. This textbook and the course of study in which you are engaged should convey a dual message—the science of genetics thas profoundly changed our understanding of life, but it is also a youthful field in the midst of a dynamic phase of its development. From classical genetics to medical genomics Meet pationt VII (Figure 1-1). Her name is Louise Benge, and as a young woman, she developed a crippling illness, Starting in her early 20s, she began to experience Louise Benge has an undiagnosed disease FIGURE 1-14 (@) Louise Benge develoned an unckagnosed disease as 2 young wornan, (b An Xray reveated that Louise Benge’s disease condition caused calieation othe ‘roi in aries [leanne Mosath, MGR ganorago: fy Natena Hmen Garam 1.8 Genetics Today 15 excruciating pain in her leg after walking as Hie a @ ty bloc, Ait, she ignored the pai then spoke with her primary care physica, and later vistedalonglineof specials She was given a battery of tests and K 1375 and these revealed the problem her amar from het aorta on down to her legs were calcified, clogged with cal- 11 cium phosphate deposits (Figure 1-14b). It was a disease forwhich her doctors had no name and no therapy. She had a disease, but ne a Gagnass There was only one thing let to ‘dey her primary eave physian reflred Benge to the Undiagnosed Dicaes rogram (UDF) at ‘the National Institutes of Health in Bethesda, Maryland. The UDP isa group of MDs and scents that has connections with specialists throughout the Netoral —V Institutes of Health in every imaginable field of medi- Cine This the eam that sted tack the most chal lenging cases. Working with Benge, the UDP team VI subjected her to nearly every test in their arsenal, and toon they found the underying defect that caused her disease, Benge had avery low level of an enzyme elle {CD73 This enzymes inven signaling between cll tnd special it send a signal da blocks cleicaon. Now the UDP doctors FIGURE 1-18 Fan too posto oul give Benge a diagnosis They named her disease “arterial caletcation due to rome Metco re meant see orceraee nnd Grrocastg atoll efeaion dat ‘What inrigued the UDP team abou Beng’ case was tha she was not alone rey COPS AGDOy Sas a, inhavng his disease Bengehad wrobrothersandwosiseryandallofthem had NC. he lesa ores, Hero arterial calticaion, Remarkably, howerey, Beng’s parents were umafeced, uecomecing ama ad fri Moreove, Benge and her siblings all had children and one ofthese childrenhad farce rureras arterial caletcation, This pater of inheritance suggested thatthe underlying, Sosatogonecton, Nabe rrreras Cause might be genetic. Specially it suggested that Benge and allofher siblings dotrate eva wit qorerators inherited two defective copies of ether CD73 ora gene that influences CD73 Hal ed oquaos orc rdatoan expression—one from their mother and one from their father. A person with one "

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